Topical pharmaceutical formulations containing a low concentration of benzoyl peroxide in suspension in water and a water-miscible organic solvent

ABSTRACT

An aqueous formulation for topical application to the skin comprising water, a water-miscible organic solvent, and benzoyl peroxide, wherein the concentration of the organic solvent is sufficient to provide a stable suspension of benzoyl peroxide in the aqueous formulation without the inclusion of a surfactant in the formulation, wherein the ratio of concentrations of water and organic solvent in the formulation is sufficient to maintain the benzoyl peroxide in saturated solubility in the formulation following application to the skin, and wherein the concentration of benzoyl peroxide in the formulation is less than 5.0% and at least 1.0% w/w. The formulation may further contain a chemical compound in addition to benzoyl peroxide that is effective in the treatment of acne. The aqueous formulations of the invention are useful in the treatment of acne and acne rosacea.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/260,211, filed Apr. 23, 2014; which is a continuation-in-part of U.S.application Ser. No. 13/613,401, filed Sep. 13, 2012; which is adivision of U.S. application Ser. No. 12/455,525, filed Jun. 3, 2009;which claims priority from U.S. Provisional Patent Application Ser. No.61/131,014, filed Jun. 5, 2008; which applications are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The present invention pertains to the field of topically appliedpharmaceutical formulations for the treatment of dermatologicconditions. In particular, the invention pertains to formulationscontaining benzoyl peroxide and optionally an anti-acne compound such asan antibiotic.

BACKGROUND OF THE INVENTION

Benzoyl peroxide is commonly used in topical pharmaceutical formulationsto treat dermatologic conditions such as acne vulgaris, commonlyreferred to as acne. Topically applied antibiotics have also been usedin topical formulations to treat dermatologic conditions such as acne.Examples of antibiotics that have been used topically to treat acneinclude macrolide antibiotic such as erythromycin and lincomycin-typeantibiotics such as clindamycin and lincomycin.

Combination products containing benzoyl peroxide and an antibiotic havebeen utilized and provide increased anti-acne efficacy compared toformulations containing either benzoyl peroxide or an antibiotic alone.Klein, U.S. Pat. No. 4,497,794, discloses a combination formulationcontaining benzoyl peroxide and erythromycin for the treatment of acne.Compositions prepared generally as described in Klein '794 are marketedunder the tradename Benzamycin® (Dermik Laboratories, Berwyn, Pa.).Combinations of benzoyl peroxide and lincomycin family antibiotics suchas clindamycin are disclosed in Klein, U.S. Pat. No. 5,767,098, Baroody,U.S. Pat. No. 5,733,886, and Stiefel, U.S. Pat. No. 5,466,446.Compositions prepared generally as described in Klein '098 are marketedunder the tradename Benzaclin® (Dermik Laboratories) and as described inStiefel are marketed under the tradename Duac® (Stiefel Laboratories,Inc., Coral Gables, Fla.).

One of the problems associated with topical therapy with compositionscontaining benzoyl peroxide, either alone or in combination with anantibiotic, is the localized irritation at the site of application.Benzoyl peroxide has been shown to have a concentration dependentirritation potential. See Mills et al, International Journal ofDermatology, 25(10):664-667 (1986) and Lassus, Current Medical Researchand Opinion, 7(6):370-373 (1981). Each of the above products containsbenzoyl peroxide at a concentration of 5% w/w, a concentration that isassociated with irritation.

Benzoyl peroxide is practically insoluble in water. The irritation dueto application of compositions containing benzoyl peroxide has beendetermined to be caused by the portion of the benzoyl peroxide that isin suspension, whereas dissolved benzoyl peroxide causes little or noskin irritation. See, Schwarz, U.S. Pat. No. 7,153,888; and De Villez,U.S. Pat. No. 4,923,900. Schwarz discloses a composition containingbenzoyl peroxide wherein all of the benzoyl peroxide of the compositionis in solution in an organic solvent. Because dissolution of benzoylperoxide accelerates the degradation of benzoyl peroxide, Schwarzdiscloses that an antioxidant is included in the composition to improvethe stability of the solution.

One disadvantage of Schwarz is that a high concentration of organicsolvent is required in order to dissolve the benzoyl peroxide. Highconcentrations of organic solvents have a tendency to be irritating toskin, primarily due to the drying effect due to solubilization of skinlipids. In Tables 1 to 3, Schwarz discloses multiple examples ofcompositions containing various organic solvents and benzoyl peroxide.In each of the examples, the concentration of organic solvent is morethan 10 times, and generally more than 15 times that of the benzoylperoxide in the composition.

De Villez discloses a composition containing benzoyl peroxide, water,and a water-miscible organic solvent that is less volatile than waterand in which the benzoyl peroxide is soluble. Prior to application onthe skin, the benzoyl peroxide is in suspension in the composition.However, when applied to the skin, the water from the compositionevaporates relatively rapidly compared to the organic solvent. Thebenzoyl peroxide of the composition is then dissolved in situ in theorganic solvent, resulting in a solution of benzoyl peroxide after allof the water has evaporated.

In order for the De Villez composition to be transformed from asuspension to a solution, the composition must remain in residence onthe skin surface for a sufficient time for the water in the compositionto evaporate. During this time, the benzoyl peroxide is in suspension inthe composition and the suspended particles are able to interact withthe skin to cause irritation. Moreover, De Villez, like Schwarz,requires a relatively high concentration of an organic solvent, whichmay contribute to the irritation potential of such compositions.

DESCRIPTION OF THE INVENTION

It has been surprisingly discovered that substantially similar clinicalanti-acne efficacy obtained by use of an aqueous topical formulationcontaining 5.0% benzoyl peroxide is obtained by providing an aqueoustopical formulation containing a suspension of a low concentration ofbenzoyl peroxide in a saturated solution of water and a water-miscibleorganic solvent. All % concentrations in this specification refer to %w/w. The formulation of the invention reduces skin irritation due toapplication of the formulation compared to application of a similar 5.0%benzoyl peroxide formulation without compromising clinical efficacy.

In one embodiment, the invention is a pharmaceutical formulation fortopical application containing water, a water-miscible organic solvent,wherein the ratio of concentrations of the water and the organic solventis high, and benzoyl peroxide, wherein the concentration of benzoylperoxide in the formulation is low. As used herein, the term “lowconcentration”, when referring to the concentration of benzoyl peroxidein a formulation, means less than 5.0% w/w. Preferably, thepharmaceutical formulation is an aqueous gel formulation. Preferably,the pharmaceutical formulation is free of surfactants.

The benzoyl peroxide is distributed in the formulation as a uniformsuspension. Preferably, the suspended benzoyl peroxide has a meanparticle size of less than 100 microns, more preferably between 1 and 50microns, and most preferably between 2.5 and 30 microns Necessarily, aportion of the benzoyl peroxide will also be dissolved in the organicsolvent and a small portion of the benzoyl peroxide will be dissolved inthe water. Accordingly, the formulation is a saturated solution ofbenzoyl peroxide with a dissolved concentration of benzoyl peroxide thatis higher than when dissolved in water without the organic solvent.

In a preferred embodiment, but not necessarily, the formulation of theinvention contains at least one additional chemical compound that iseffective in the treatment of acne. The anti-acne compound may besuspended or dissolved in the formulation. Preferably, the anti-acnecompound is soluble in water and so is dissolved in the formulation. Onesuch preferred anti-acne compound is an antibiotic. Preferredantibiotics include those of the macrolide family of antibiotics such aserythromycin, azithromycin, clarithromycin, tilmicosin, and tylosin, andthose of the lincomycin family of antibiotics such as clindamycin andlincomycin. A particularly preferred antibiotic to be used incombination with benzoyl peroxide in the formulation of the invention isclindamycin, such as clindamycin hydrochloride or clindamycin phosphate.Additional topical anti-acne active ingredients that may be contained inthe formulation of the invention, either with or without the inclusionof an antibiotic, include salicylic acid, azelaic acid, niacinamide,urea, and retinoids such as tretinoin, adapalene and tazarotene.

The additional anti-acne compound, if present in the formulation of theinvention, is preferably present in a concentration in which there is ademonstrable anti-acne effect in the absence of benzoyl peroxide. Forexample, if clindamycin is present in the formulation of the invention,the concentration of the clindamycin is preferred to be at least 0.5%with a preferred concentration of 1%. Higher concentrations ofclindamycin, such as 2.5% or 5.0% or higher may be utilized in theformulation.

The organic solvent of the formulation of the invention has thefollowing characteristics:

-   -   (1) is miscible in water,    -   (2) does not chemically react with benzoyl peroxide at        temperatures between 0° C. and 40° C.,    -   (3) is a liquid at temperatures between 0° C. and 40° C.,    -   (4) is capable of dissolving benzoyl peroxide at a concentration        of at least 0.1% at an ambient temperature,    -   (5) is capable of dispersing benzoyl peroxide in an aqueous gel        in the absence of a surfactant.

An example of a preferred organic solvent for the formulation of theinvention is a polyol, also known as a polyhydric alcohol.Representative examples of polyols include glycols and sugar alcohols.Preferred polyols for the formulation of the invention include polyetherglycols, such as ethoxydiglycol, and propylene glycol. A preferredwater-miscible organic solvent is propylene glycol. The inventors havedetermined by HPLC analysis that benzoyl peroxide is soluble in 100%propylene glycol at room temperature at a level between 0.2% and 0.3%w/w. A second preferred organic solvent is ethoxydiglycol, such as soldunder the tradename Transcutol® (Gattefosse, Saint-Priest, France). Ithas been determined by HPLC analysis that benzoyl peroxide is soluble inethoxydiglycol at room temperature at a level of about 4.9%. Anotherpreferred organic solvent is polyethylene glycol, such as PEG 400.

The concentration of the organic solvent in the formulation should besufficiently high to provide a stable suspension of benzoyl peroxide inan aqueous fluid without the presence of a surfactant. The concentrationof the organic solvent should be lower than that which will dissolve allof the benzoyl peroxide in the formulation following the removal of allof the water from the formulation. Generally, the concentration of theorganic solvent should be between one and four times the concentrationof benzoyl peroxide in the formulation.

Additionally, the ratio of concentrations of water and organic solventin the formulation should be high, so as to maintain the benzoylperoxide at or near saturated solubility in the residual formulation,that remaining on the skin after application of the formulation withsubsequent evaporation of water from the formulation, thereby maximizingthe thermodynamic activity of the benzoyl peroxide in the residualformulation on the skin. It is therefore preferred that, in theformulation of the invention, the relative concentrations of water andthe organic solvent should be at least 7:1, such as at least 9:1 or10:1, preferably at least 12:1, and most preferably at least 20:1, suchas up to 98:1.

The concentration of benzoyl peroxide in the formulation is an amountthat is less than 5.0% and that is effective to treat the signs and/orsymptoms of acne. At the concentrations of benzoyl peroxide in theformulation of the invention, skin irritation is reduced compared toformulations containing 5.0% benzoyl peroxide. Therefore, concentrationsof benzoyl peroxide between 1.0% and 4.5% are suitable for invention. Apreferred range of benzoyl peroxide concentrations is between 2.0% and3.5%. Another preferred range of benzoyl peroxide concentrations isbetween 3.5% and 4.0%. A most preferred concentration of benzoylperoxide is about 2.5%, that is between 2.3% and 2.7%. Another mostpreferred concentration of benzoyl peroxide is about 3.75%, that isbetween 3.6% and 3.9%.

The formulation may be one of many topical formulation types containingwater as the major ingredient, including solutions, gels, creams, spraysand foams. It is preferred, although not required, that the formulationbe in the form of an aqueous gel. Accordingly, the formulation of theinvention may contain a gelling or thickening agent. Any gelling agentthat is water-dispersible, is suitable for use on epithelial tissue suchas skin, and forms an aqueous gel of substantially uniform consistency,is suitable for use in the composition of the invention. One preferredgelling agent is hydroxypropylcellulose, such as that sold under thetradename KLUCEL® (Hercules Incorporated, Wilmington, Del., USA).Another preferred gelling agent is hydroxyethylcellulose, such as thatsold under the tradename NATROSOL® (Hercules Incorporated). Othersuitable gelling agents include carboxyvinyl polymers, also known ascarbomers, such as are sold under the tradename CARBOPOL® 934, 940, 941,980, and 981 (B.F. Goodrich Co., Akron, Ohio, USA), ETD 2020™, andULTREZ® (Noveon, Inc., Cleveland, Ohio, USA). Additional suitablegelling agents are polyvinyl alcohol, polyethylene oxides, propyleneglycol alginates, methylcellulose, hydroxypropylmethylcellulose andnatural polymeric gums such as xanthan, and carrageenan. Theconcentration of gelling agent in the composition may be varieddepending on several factors, including the desired degree ofstabilization of the BPO suspension and desired viscosity of the gelcomposition.

If desired, the formulation of the invention may further includeadditional pharmaceutically acceptable excipients typically used informulations and known to those skilled in the art. Such excipientsinclude, for example, humectants, emollients, pH stabilizing agents,preservatives, chelating agents, and anti-oxidants.

The formulation of the invention can be used to treat acne by applyingthe formulation to affected areas of the skin, such as on the face,neck, back, and chest. The formulation is preferably applied one or moretimes daily for a time sufficient to ameliorate the signs of acne. Ithas been surprisingly discovered that formulations of the inventioncontaining 2.5% benzoyl peroxide or 3.75% benzoyl peroxide have efficacyin treating acne that is comparable to that obtained with formulationscontaining 5.0% benzoyl peroxide, the preparations also containing anantibiotic, clindamycin 1%. It is further surprising that thiscomparable efficacy was observed when the formulations of the inventionwere applied only once daily and the formulations containing 5.0%benzoyl peroxide were applied twice daily. Unexpectedly, a formulationcontaining 3.75% benzoyl peroxide was found to exhibit efficacycomparable to, or better than, that of a formulation containing 5%benzoyl peroxide in treating acne while maintaining an adverse eventprofile comparable to a formulation containing 2.5% benzoyl peroxide.

The formulation of the invention may also be used in the treatment ofacne rosacea. In treating acne rosacea, the formulation of the inventionis applied to affected areas, preferably one or more times daily for atime sufficient to ameliorate the signs and symptoms of acne rosacea.

The formulation of the invention may be made by any means by which thecomponents of the invention are combined to provide a pharmaceuticalformulation. For example, a suspension of benzoyl peroxide may be madeby combining water, the water-miscible organic solvent, and benzoylperoxide. Preferably, the combination is mixed, such as by stirring,sonicating, milling, and/or shaking, to produce a uniform suspension ofbenzoyl peroxide particles in the water and organic solvent. Additionalingredients, such as a gelling agent and other excipients, may be addedeither before or after the uniform suspension is obtained.

If an additional anti-acne medication is included in the formulation, itmay be combined with the other components prior to or after forming thesuspension of benzoyl peroxide. An alternative is to provide a separateaqueous solution of the anti-acne medication, such as clindamycin, andcombine this solution with the benzoyl peroxide suspension to obtain afinal formulation.

The invention is further illustrated in the following examples which aremeant to be exemplary and not limiting.

EXAMPLE 1 Exemplary Formulation of the Invention

A pharmaceutical formulation of the invention was made containing thefollowing components as shown in Table 1.

TABLE 1 COMPONENT % w/w Benzoyl peroxide 2.5 Propylene glycol 5.0Carbopol 980 ® 1.75 Potassium hydroxide 0.5 Water QS 100 (90.25)

EXAMPLE 2 Additional Exemplary Formulations of the Invention

Two pharmaceutical formulations of the invention containing an anti-acnemedication in addition to benzoyl peroxide was made containing thefollowing components as shown in Table 2.

TABLE 2 Formulation A Formulation AA COMPONENT (% w/w) (% w/w) Benzoylperoxide 2.5 3.75 Propylene glycol 5.0 5.0 Clindamycin phosphate 1.2*1.2 Carbopol 980 ® 1.75 1.75 Potassium hydroxide 0.5 0.5 Water QS 100(89.05) QS 100 (87.8) *equivalent to 1.0% clindamycin

EXAMPLE 3 Comparative Efficacy

The aqueous gel formulation of Example 2 containing 2.5% benzoylperoxide, 5% propylene glycol, 89% water, and 1% clindamycin was testedfor efficacy in the treatment of acne lesions in a large clinical studyin which 399 patients were treated. This formulation of the invention isFormulation A. A similar aqueous gel formulation containing 5.0% benzoylperoxide, 10% propylene glycol, 82.5% water, and 1.0% clindamycin wasmade and tested for efficacy in the treatment of acne lesions in asecond clinical study of very similar design. This formulation, which isnot of the invention, is Formulation B. These results were compared withdata provided in the prescribing information on the efficacy of anaqueous gel commercial product containing 5.0% benzoyl peroxide, 1%clindamycin, dioctyl sodium sulfosuccinate (surfactant), and water(BenzaClin® Topical Gel, Dermik Laboratories, Bridgewater, N.J.). Thisprior art formulation is Formulation C. Formulations A and B containedno surfactant. Formulation A was applied only once daily whereasFormulations B and C, each of which contain 5.0% benzoyl peroxide, wereapplied twice daily during the 12 week treatment period. Formulation Awas tested after 12 weeks of application. The data for Formulations Band C is following 10 weeks of application. A formulation containing3.75% benzoyl peroxide, Formulation AA, was also tested according to theprocedure for Formulation A. Formulation AA also contained propyleneglycol (5.0% w/w), clindamycin phosphate (1.2% w/w), Carbopol 980®(1.75% w/w), potassium hydroxide (0.5% w/w), and water (QS 100%).Formulation AA contained no surfactant.

Test subjects were instructed to apply the formulation to the face,either twice daily for

Formulations B and C or once daily for Formulations A and AA. After 10weeks for Formulations B and C, and after 12 weeks for Formulations Aand AA, the mean percent reduction in inflammatory lesions andnon-inflammatory acne lesions was determined. The percentage reductionin inflammatory lesions (pustules and papules) was calculated bysubtracting the total inflammatory lesion counts at the end of the study(10 or 12 weeks) from the baseline total inflammatory lesion counts,times 100, and divided by the baseline total inflammatory lesion counts.Non-inflammatory lesions comprised open comedones and closed comedones,and the percentage reduction in non-inflammatory lesions was calculatedin the same way. The results of this acne study are shown in Table 3.

TABLE 3 Formulation Formulation Formulation Formulation A B C AA Numberof 399 481 215 253 Subjects Mean % 48.8 59.2 53.5 60.6 Reduction inInflammatory Acne Lesions Mean % 42.6 51.0 36.1 51.6 Reduction in Non-inflammatory Acne Lesions

The data of Table 3 shows that the efficacy of Formulation A containingonly 2.5% benzoyl peroxide was similar to that of Formulations B and C.These results are especially surprising in view of the fact thatFormulation A was applied only once daily whereas Formulations B and Cwere applied twice daily. Formulation AA containing 3.75% benzoylperoxide and 1.2% clindamycin phosphate exhibited higher efficacy thanthe Formulation A containing 2.5% benzoyl peroxide and 1.2% clindamycinphosphate. Surprisingly, Formulation AA also exhibited higher efficacythan Formulations B and C containing 5% benzoyl peroxide.

EXAMPLE 4 Irritation Potential

Formulations A and B of Example 3, each containing benzoyl peroxide and1.0% clindamycin, were tested to determine the comparative irritationpotential of these two formulations. Formulation A of the inventioncontains 2.5% benzoyl peroxide, propylene glycol at two times theconcentration of the benzoyl peroxide, and water at a concentration 17.8times that of the propylene glycol. Formulation B contains 5.0% benzoylperoxide, propylene glycol at two times the concentration of the benzoylperoxide, and water at a concentration 8.25 times that of the propyleneglycol.

Gel formulations A and B were applied under separate occlusive patchesto the backs of 33 healthy subjects three times a week for three weeks.Each application was observed 48 hours following each application forsigns of irritation or inflammation by evaluators and assigned a scoreusing a standardized grading system for irritation on a severity scaleof 0 (no sign of irritation) to 4 (erythema with edema and blistering).Data from this study shows that use of Formulation A of the inventionproduced a 33% decrease in overall cumulative irritation score comparedto use of Formulation B.

In addition, Formula A and Formulation AA exhibited similar adverseevent profiles. The expectation was that the number of subjectsreporting adverse events (for example, redness, itching, and burning)would be higher for Formulation AA, having a higher concentration ofbenzoyl peroxide, than for Formulation A. The unexpected results ofcombination AA are shown in Table 4. The number of subjects reportingone or more adverse events were similar for Formulation A andFormulation AA, and both formulations were similar to vehicle.

TABLE 4 Formulation Vehicle AA AA Formulation A Vehicle A Number ofSubjects 243 236 386 188 Number of subjects who 54 of 243 57 of 236 106of 386 50 of 188 reported one or more adverse (22.2%) (24.2) (27.5)(26.6) events Number of adverse events 4 of 68 7 of 71  5 of 139 4 of 78related to or possibly related to (5.8%) (9.9%) (3.6%) (5.1%) studymedication^(a) ^(a)Based on total number of events.

Further modifications, uses, and applications of the invention describedherein will be apparent to those skilled in the art. It is intended thatsuch modifications be encompassed in the above description and in thefollowing claims.

1-14. (canceled)
 15. An aqueous formulation for topical application tothe skin comprising about 3.75% w/w benzoyl peroxide, about 5.0% w/wpropylene glycol, about 1.2% w/w clindamycin phosphate, about 1.75% w/wCARBOPOL 980® and about 87.8% w/w water.
 16. The aqueous formulationaccording to claim 15, wherein benzoyl peroxide is distributed in theformulation as a uniform suspension.
 17. The aqueous formulationaccording to claim 16, wherein the suspended benzoyl peroxide has a meanparticle size of less than 100 microns.
 18. The aqueous formulationaccording to claim 16, wherein the aqueous formulation is free ofsurfactant.
 19. The aqueous formulation according to claim 16, whereinthe aqueous formulation comprises a surfactant.
 20. A method fortreating acne comprising applying once a day for up to 12 weeks to theskin of a patient in need thereof an aqueous formulation according toclaim
 15. 21. The method according to claim 20, wherein the aqueousformulation is applied to the face, neck, back, or chest of the patient.22. The method according to claim 20, wherein the aqueous formulation isfree of surfactant.
 23. The method according to claim 20, wherein theaqueous formulation comprises a surfactant.
 24. A method for treatingacne rosacea comprising applying to the skin of a patient in needthereof an aqueous formulation according to claim 15 one or more timesdaily for a time sufficient to ameliorate the signs and symptoms of acnerosacea.
 25. The method according to claim 24, wherein the aqueousformulation is free of surfactant.
 26. The method according to claim 24,wherein the aqueous formulation comprises a surfactant.